1. Field of the Invention
This invention relates to a series of selective lithium chelators, e.g. ionophores, and to their uses.
Ionophores are complexing agents which are capable of reversibly binding ions. Such ion-selective materials can be used in sensors for the direct measurement of ions, in this case lithium ions. For example, the concentration of lithium ions in biological fluids such as blood, may be monitored. Also, the selectivity of these complexes for lithium ions can be used to selectively remove lithium ions from aqueous solutions including lithium and other metal cations, such as encountered in the recovery of pure lithium from its ores.
Lithium carbonate is typically used as an anti-manic drug. The main mechanism for excretion of excess lithium is through the kidneys. Unfortunately, in some patients this mechanism is not sufficient, resulting in an initial rise in lithium concentration to toxic levels. Moreover, since the therapeutic dosage (0.6-1.2 mmol/L) is close to toxic levels (1.5-2 mmol/L), lithium toxicity is common. Overdose symptoms include sluggishness, drowsiness, coarse tremors, vomiting, thirst, diarrhoea, blurred vision, confusion, increasing disorientation, seizures, and sometimes coma and death.
Moreover, since there is not much difference between therapeutic and toxic lithium levels it is desirable to name a simple and convenient method of monitoring lithium levels in the bloodstream. Lavage and activated charcoal (charcoal does not adsorb lithium effectively) can reduce lithium present in the gastrointestinal tract, but not the lithium present in the bloodstream. Since some patients have a low rhinal excretion rate for lithium, diuretics have limited use. Moreover, forced diuresis is a severe treatment which can disrupt the serum ion balance, and may cause infection.
Various methods are also known in the art for removing metal ions from aqueous solutions. For example, in Canadian Patent No. 1,221,499 of 5 May 1987 in the names of M. Corvette et. al., macroporous alkylaminophosphonic chelating resins are disclosed for removing calcium and magnesium from brines.
Also, in Canadian Patent no. 606,439 in the name of H. R. Lukens, metals other than alkali metals, may be usefully complexed with chelating polymers for stabilization of fuels. Specifically, by chelating the metal with a copolymer of a vinyl ester of a lower molecular weight alkyl carboxylic acid and an acyclic alpha-monoolefinic hydrocarbon.
A complex of the ligand N(CH.sub.2 CH.sub.2 py).sub.3, wherein py is 2-pyridyl, with copper ions, is known for example, from Synthesis and X-ray Structural Characterization of Cu(I) and Cu(II) Derivatives, K. D. Karlin et. al., Inorganica Chimica Acta. 64(1982) L219-L220.
A similar ligand i.e. N(CH.sub.2 py).sub.3, is known from Pyridine Derivatives, G. Anderegg and F. Wenk, Helvetica Chimica Acta. Vol. 50, Chapter 8 (1967)-No. 243, p. 2330-2332.
There is no teaching or suggestion in any of these references of the use of such ligands for selective removal of lithium ions from aqueous solutions, such as biological fluids e.g. gastro-intestinal fluids, blood and serum. It will also be appreciated from these references that the alkali metals, such as lithium have different complexing properties than other metals, and that there is no requirement for low toxicity in such environments.
At present, detection of Li.sup.+ in aqueous solution involves AA, ICP, DCP or ion selective electrodes. Ion selective electrodes suffer from interference problems namely from Na.sup.+, K.sup.+ and Ca.sup.+2. [Gadzepko. V. P. Y., et. al., Ion Selective Electrode Rev., 1986, 8, 173-207]. These interferences make ion selective electrodes for lithium, inadequate to the present, for application to biological fluids. The other methods, although more selective, are expensive and require bulky instruments.